Pharmaceutical compositions providing potassium chloride in aqueous solution

ABSTRACT

Aqueous solutions containing potassium chloride, useful for the treatment of hypokalaemia, are obtained by dissolving in water or an aqueous medium compositions comprising a mixture of a solid, water-soluble hydrochloride of a physiologically innocuous nitrogen-containing organic compound e.g. betaine hydrochloride, which dissociates an addition to water to yield an acid solution containing hydrochloric acid and the organic base, and at least one of potassium bicarbonate and potassium carbonate.

United States Patent 11 1 Corker [111 3,708,574 51 1Jan.2,1973

[54] PHARMACEUTICAL COMPOSITIONS PROVIDING POTASSIUM CHLORIDE IN AQUEOUSSOLUTION [75] Inventor: Alfred Eric Corker, Brighton,

Eng q [73] Assignee: Arthur H. Cox & Co., Limited, Brighton, England[22] Filed: Oct. 13, 1970 [21] Appl. No.: 80,469

Related US. Application Data [63] Continuation of Ser. No. 722,544,April 19, 1968,

abandoned.

[30] Foreign Application Priority Data April 28, 1967 Great Britain..l9,796/67 [52] US. Cl ..424/44, 424/316 [51] Int. Cl. ..A6llr 9/00[58] Field of Search ..424/316, 319, 44

[56] References Cited UNITED STATES PATENTS 3,337,404 8/1967 Polli eta1. ..424/44 2,798,837 7/1957 Sahyun ..424/316 OTHER PUBLICATIONSRemington's Practice of Pharmacy, 12th Edition, 1961 pp. 662, 728, 781.

The Merck Index 1960 pp. 147, 431, 484, 486, 487, 490, 607 and 920.

Greenstein et a1. Chemistry of the Amino Acids 1956 Vol. 3.

New Drugs, 1966 p. 265-267.

Primary Examiner-Albert T. Meyers Assistant Examiner-Norman A. DrezinAttorney-Cushman, Darby & Cushman [57] ABSTRACT Aqueous solutionscontaining potassium chloride, useful for the treatment of hypokalaemia,are obtained by dissolving in water or an aqueous medium compositionscomprising a mixture of a solid, water-soluble hydrochloride of aphysiologically innocuous nitrogencontaining organic compound e.g.betaine hydrochloride, which dissociates an addition to water to yieldan acid solution containing hydrochloric acid and the organic base, andat least one of potassium bicarbonate and potassium carbonate.

1 Claim, No Drawings PHARMACEUTICAL COMPOSITIONS PROVIDING POTASSIUMCHLORIDE IN AQUEOUS SOLUTION CROSS-REFERENCE TO RELATED APPLICATIONSThis is a continuation of earlier application Ser. No. 722,544 filedApril 19, 1968, now abandoned.

THIS INVENTION relates to pharmaceutical compositions and, moreparticularly, to compositions in tablet form which can readily be usedfor the production of potassium chloride for oral administration.

In many treatments of patients, for example in the treatment of edemaand hypertension with some diuretics, it is necessary to replaceexcreted potassium by the administration of potassium in an assimilableform. This is usually effected by the oral administration of potassiumchloride, in the form either of uncoated tablets, or of enteric coatedtablets. Both methods, however, have disadvantages which render themunsuitable in particular cases. Uncoated tablets of potassium chlorideoften take a long time to dissolve and produce a solution of potassiumchloride in the stomach which many patients find nauseating. Entericcoated tablets have a variable solubility and may, in fact, pass throughthe body without dissolving. Moreover, with both uncoated and ent'ericcoated tablets, there is a danger that the tablet may adhere to theintestinal mucosa and produce a high local concentration of potassiumchloride which may lead to intestinal ulceration. 1

In order to avoid these disadvantages, it has been proposed toadminister the potassium as a salt other than potassium chloride, forexample as potassium citrate or tartrate. The use of such salts,however, introduces the danger of creating an alkalosis in the patient.

Moreover, it is known that diuretic drugs encourage the excretion ofchloride ion, and it has been found in practice that in the presence ofa chloride deficiency it is not possible to replace a potassiumdeficiency unless the chloride deficiency is replaced simultaneously. Insuch circumstances, therefore, the potassium cannot be assimilatedunless it is associated with chloride ions.

Another approach to the problem has been the use of so-called slowrelease tablets of potassium chloride in which the potassium chloride isslowly released during the passage of the tablet through the alimentarytract. While the use of such tablets may be effective in preventing theformation of a nauseous concentration of potassium chloride in thestomach, they still are open to the objection that they may adhere tothe intestinal wall and cause ulceration.

It is the object of the present invention to provide pharmaceuticalcompositions which can be used to provide potassium chloride in anorally admiuistrable form, for the treatment of hypokalaemia (with orwithout associated hypochloraemia) and, at the same time, not causingnausea in the patient or ulceration or stenosis of the wall of thealimentary tract.

According to the present invention, there are provided pharmaceuticalcompositions comprising a mixture of solid, water-soluble hydrochlorideof a physiologically innocuous nitrogen-containing organic compoundwhich dissociates on addition to water to yield an acid solutioncontaining hydrochloric acid and the organic base, and at least one ofpotassium bicar bonate and potassium carbonate, the compositionsproducing on addition'to water an effervescent solution containingpotassium chloride. Preferably potassium bicarbonate alone is employedin the mixture because of the tendency for potassium carbonate todeliquesce. By the term physiologically innocuous nitrogencontainingorganic compound is meant a compound which when administered orally inaqueous solution to a patientcauses substantially no undesirable effectsin the patient. Suitable hydrochlorides of nitrogen-containing organiccompounds are those of (a) a number of amino-acids, namely: glycine,alanine, phenylalanine, leucine and glutamic acid, and other aandB-amino-acids containing carbon, hydrogen, oxygen and nitrogen only andnot more than six carbon atoms; (b) N-alkyl substituted derivatives ofglycine or its homologues of the formula:

wherein the]! symbols are the same or different and each represents analkyl group containing not more than 4 carbon atoms (preferably methylor ethyl) and n represents an integer of from 1 to 3, for examplebetaine, i.e. the trimethyl derivative of glycine, and triethyl glycine;o) the methyl, ethyl, propyl, isopropyl and benzyl esters of glycine,alanine, phenylalanine, leucine and glutamic acid, including thedimethyl and diethyl esters of glutamic acid; (d) amides of alanine,phenylalanine, glycine and glutamic acids; (e) N- methyl, N ,N-dimethyl,N-ethyl and N,N-diethyl derivatives of glycine, alanine, phenylalanineand glutamic acids; (f) alkyl esters of betaine, or the N -methyl, N,N-dimethyl, N-ethyl or N,N-diethyl derivative of glycine, containing oneto three carbon atoms in the alkyl radical, and (g) methyl and ethylglucosamines. The references to glutamic acid in this specification andaccompanying claims includes all isomers of the acid.

The particularly preferred hydrochloride incorporated in thecompositions of the invention is betaine hydrochloride. Otherhydrochlorides which, in addition to betaine hydrochloride, maypreferentially be incorporated in the compositions of the invention arethe hydrochlorides of glycine, N-methyl-, N-ethyl-, N,N- dimethyland N,N-diethyl-glycine and the methyl and ethyl esters of these fiveamino-acids, alanine or B- phenylalanine hydrochloride, glutamic acidhydrochloride, glutamic acid mono methyl or ethyl ester hydrochloride,glutamic acid'dimethyl or diethyl ester hydrochloride, N-met hylglutamicacid hydrochloride, alanine amide hydrochloride and glycine amidehydrochloride.

The compositions are advantageously in the form of tablets; however,they may also be in the form of powders or granules in paper packets,sachets or other pharmaceutical preparation forms for single dosageunits of solid compositions. The compositions will usually also containa sweetening agent, for example a sugar, saccharin or an alkali metal(e.g. sodium) derivative thereof, or cyclamic acid or salt thereof(preferably calcium cyclarnate), and/or a flavoring agent suchas oil ofpeppermint, to assist acceptance of an aqueous solution of thecomposition by the patient.

Preferably they contain a combination of calcium cyclamate andpeppermint oil in suitable proportions. When the compositions of theinvention are to be in tablet form, a binding agent, which isadvantageously a high molecular weight polyvinyl pyrrolidone, and smallamounts of a lubricating agent, such as stearic acid and/or magnesiumstearate, are incorporated in the compositions to facilitate tablettingof the ingredients.

The compositions of the invention are added to, and dissolved in, waterbefore oral administration to a patient. On'dissolution in water thehydrochloric acid liberated by dissociation of the hydrochloride of thenitrogen-containing organic compound reacts with the potassiumbicarbonate or carbonate to form potassium chloride and gaseous carbondioxide, which causes effervescence. The aqueous potassium chloridesolution thus formed can be administered orally and has been found notto produce nausea. This may be due, at least in part, to the effect ofthe gaseous carbon dioxide simultaneously formed in the solution.Moreover, dissolution of the compositions in water, accompanied byeffervescence and providing a palatable, drinkable solution, preventsthe production of local concentrations of potassium chloride in thealimentary tract and thus avoids possible ulceration there. The freeorganic base simultaneously present in the formed aqueous solution,being physiologically innocuous, does not have any harmful effects onthe patient; betaine has, so far, been found to be best in that respect.

The amounts of hydrochloride of the nitrogen-containing organic compoundand potassium salt included in the compositions can be varied accordingto what is required in the aqueous solution to be administered. If it isrequired to produce potassium chloride in effervescent solution with nosurplus potassium or chloride ion (i.e. 1 mole of potassium ion per moleof chloride ion), this is achieved by incorporating the substances inthe theoretical proportions for quantitative reaction, producing onlypotassium chloride and the free nitrogen organic base. On the otherhand, if it is required for any particular purpose to provide an excessor a deficiency of either the potassium or the chloride ion, theproportions of the two ingredients in the mixture can be variedaccordingly. On addition to water of such mixtures, in which thequantities of potassium salt and hydrochloride are not in balance, therecan be obtained in solution the required quantity of potassium chloridetogether with either an excess of the original unaltered potassium saltor an excess of the hydrochloride providing the chloride ion.

The preferred compositions of the invention are those in which thehydrochloric acid source, i.e. the hydrochloride, provides in aqueoussolution 1 mole of hydrogen chloride to react with 1 mole of potassiumbicarbonate, or two or more moles of hydrogen chloride to react with 1mole of the potassium salt, depending upon the number of available atomsof potassium in the salt.

The proportion of the two essential ingredients in the compositions ofthe invention are selected so as to produce a predetermined amount ofpotassium chloride on dissolution in water. In a preferred feature ofthe invention, the compositions are in the form of tablets which canproduce an aqueous solution containing about 500 mg. of potassiumchloride per tablet. A

particularly preferred formulation of the invention is a tablet havingthe composition given in the following Example.

EXAMPLE 1 betaine hydrochloride 1.035 g.

potassium bicarbonate 0.675 g.

calcium cyclamate 0.05 g. V

peppermint oil 0.004 g.

"""polyvinyl pyrrolidone (M.W. 25,000) 0.035 g. lubricants: stearic acid1% by weight magnesium stearate 1% by weight On solution in water, or anaqueous liquid, one tablet of this composition will produce 500 mg. ofpotassium chloride.

Instead of 0.675 g. of potassium bicarbonate there may be used 0.465 g.of potassium carbonate.

Further pharmaceutical compositions of the present invention are givenin the next Example.

EXAMPLE 2 Tablets are formed in the usual way, each having thecomposition:

glycine hydrochloride 0.750 g. potassium bicarbonate 0.675 g. calciumcyclamate 0.05 g. peppermintoil 0.004 g. polyvinyl pyrrolidone (NLW.25.000) 0.035 g. lubricants: stearic acid 1% by weight magnesiumstearate 1% by weight The stipulated amount of glycine hydrochloride maybe replaced by 0.855 g. of glycine methyl ester hydrochloride, 1.325 g.of methyl glutamate hydrochloride, or 1.420 g. of dimethyl glutamatehydrochloride.

EXAMPLE 3 i. An excess of one mole of chloride ion (as HCl):

3. Betaine hydrochloride 1.190 parts Potassium bicarbonate 0.675 partsb. Betaine hydrochloride 1.190 parts Potassium carbonate 0.465 parts ii.A deficiency of one mole of chloride ion (as l-lCl):

c. Betaine hydrochloride 0.880 parts Potassium bicarbonate 0.675 partsd. Betaine hydrochloride 0.880 parts Potassium carbonate 0.465 partsiii. An excess of one mole of potassium ion:

e. Betaine hydrochloride 1.035 parts Potassium bicarbonate 0.775 partsf. Betaine hydrochloride 1.035 parts Potassium carbonate 0.605 parts .5iv. A deficiency of one mole of potassium:

g. Betaine hydrochloride 1.03s parts Potassium bicarbonate 0.575 partsh. Betaine hydrochloride 1.035 parts Potassium carbonate I 0.305 partsTo such mixtures there may be added sweetening and/or flavoring agentsand optionally other ingredients usually incorporated in solidcompositions for tabletting purposes.

There may also be added to the compositions of the invention certaindiuretics, so that these can be ad-'- I l,l-dioxide] and Quinethazone[7-chloro-2-ethyll ,2,3 ,4-tetrahydro-4-oxo-6-sulphamoylquin azoline Thefollowing Example illustrates a mixture which would give 250 mgm. ofpotassium chloride in aqueous solution and which contains an appropriatedosage of diuretic. Y

EXAMPLE 4 glycine hydrochloride 0.375 g.

(or betaine hydrochloride 0.5l g.) potassium bicarbonate 0.3375 g.Hydrochlorothiazide 0.020 g. calcium cyclamatc 0.025 g. peppermint oil0.002 g. polyvinyl pyrrolidone 0.0175 g.

stearic acid 1% by weight magnesium stearate 1% by weight The dosage ofpotassium chloride administered daily to a patient utilizing thecompositions of the invention will vary greatly according to therequirements of the particular patient, but generally a dosage of from 1to 10 grams of potassium chloride, by means of 2 to 20 tablets of theinvention providing 0.5 g. ofthe solid salt in aqueous solution, issatisfactory.

l. A dry composition for the treatment of hypokalemia which comprises amixture of;

A. betaine hydrochloride, and

B. potassium bicarbonate, in an amount sufficient to cause effervescenceupon the addition of said mixture to-water, whereb a solution containinan antihypokalemie effec ive amount of po assium chloride is producedhaving an equimolar concentration of chlorideand potassium ions.

